Cancer is the second leading cause of death in the U.S. and accounts for the deaths of 1 of every 4 Americans. The American Cancer Society estimates that 556,000 Americans died from cancer in 2003. Cancer therapy is presently based on three different approaches, namely chemotherapy, radiation therapy (i.e. radiotherapy) and surgery. Radiotherapy is often used as adjuvant or secondary treatment following surgical procedures to remove a cancerous tumor or in combination with chemotherapy.
The radiotherapeutic approach to eradicating malignant cells found in cancerous tumors was first introduced during the late 1800s and is currently used with curative intent or for palliation in approximately half of all cancer patients. Radiotherapy remains a component of the standard of care for most locally advanced solid tumors. Local recurrence remains a major obstacle to achieving cure of many locally advanced solid tumors treated with definitive radiation therapy. This local recurrence translates directly into poor likelihood of long-term survival.
The ability of radiation therapy to eradicate malignant cells critically depends upon the intratumoral content of molecular oxygen, a potent radiosensitizer involved in mediating DNA damage. The microenvironment of solid tumors is hypoxic compared with normal tissue, and this hypoxia is associated with decreased radiosensitivity. Recent preclinical data suggest that intratumoral hypoxia, particularly in conjunction with an acid microenvironment, may be directly or indirectly mutagenic. Investigations of the prognostic significance of the pretreatment oxygenation status of tumors in patients with head and neck or cervical cancer have demonstrated that increased hypoxia, typically designated in these studies as pO2 levels below 2.5-10 mm Hg, is associated with decreased local tumor control and higher rates of disease and lower overall survival. Hypoxia-directed therapies in the radiation oncology setting include treatment using hyperbaric oxygen, fluosol infusion, carbogen breathing, and electron-affinic and hypoxic-cell sensitizers.
The most well-studied, hypoxia-directed strategy for cancer treatment is the use of electron-affinic radiosensitizers, which mimic the actions of oxygen but are more slowly metabolized. During the past 2 decades, the nitroimidazole compounds misonidazole, nimorazole, and etanidazole have been extensively evaluated by the Radiation Therapy Oncology Group (RTOG) and the Danish Association of Head and Neck Cancer (DAHANCA) as adjuncts to radiation therapy in carcinomas of the head and neck, cervix, and lung (Grigsby et al. Int J Radiat Oncol Biol Phys 1999; 44:513-517; Lee et al. Int J Radiat Oncol Biol Phys 1989; 16:465-470; Lee et al. Int J Radiat Oncol Biol Phys 1995; 32:567-576; Overgaard et al. Int Radiat Oncol Biol Phys 1989; 16:1069-1072; Overgaard et al. Int J Radiat Oncol Biol Phys 1989; 16:1065-1068; Overgaard Int J Radiat Biol 1989; 56:801-811; Overgaard et al. Radiother Oncol 1998; 46:135-146; Wasserman et al. Radiother Oncol 1991; 20(suppl 1):129-135. Most of these studies reported disappointing local control and survival outcomes, but a few recent studies appear to support the use of nitroimidazole compounds with radiation therapy. Other cancer treatment protocols currently employ radiosensitizers activated by ionizing radiation, e.g., X-rays. Examples of X-ray-activated radiosensitizers include, but are not limited to, the following: metronidazole, desmethylmisonidazole, pimonidazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FUdR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives of the same.
Some therapeutic compounds, which are known as being cytotoxic per se, hence susceptible of being used in the therapy of cancer, are also endowed with radiosensitization activity as they are capable of inducing DNA radiation damage in response to ionizing radiation. So far, the possibility of combining both cytotoxic agents, e.g. a given radiosensitizer and radiotherapy, with the expectation of getting a supra-additive antitumor effect in comparison to the single cytotoxic alone, is of utmost importance in cancer therapy. Among the several compounds endowed with antitumor activity and also known as possessing radiosensitization activity see, for instance, cisplatin, gemcitabine, navelbine, tomudex, nicotinamide, paclitaxel, docetaxel, simvastatin and topotecan.
We have now discovered that the chemotherapeutic activity of certain camptothecin (CPT) derivatives is enhanced by appending various electronic-affinic groups to provide a single compound for use as a chemoradiosensitizer. The compounds of the invention are considerably less toxic than camptothecin and topotecan. This invention defines a new series of radiosensitizing camptothecin derivatives that are useful for treating various types of cancer. We have also discovered that certain known CPT derivatives are useful in the process of sensitizing a subject's tumor cells to radiation, wherein the process comprises administering a CPT derivative to a subject and then exposing the tumor cells in the subject to radiation.